Rigidity And Multifocal Seizure Syndrome, Lethal Neonatal

A number sign (#) is used with this entry because of evidence that lethal neonatal rigidity and multifocal seizure syndrome (RMFSL) is caused by homozygous or compound heterozygous mutation in the BRAT1 gene (614506) on chromosome 7p22.

Biallelic mutations in the BRAT1 gene can also cause neurodevelopmental disorder with cerebellar atrophy and with or without seizures (NEDCAS; 618056), a somewhat less severe disorder with overlapping features.

Description

Lethal neonatal rigidity and multifocal seizure syndrome is a severe autosomal recessive epileptic encephalopathy characterized by onset of rigidity and intractable seizures at or soon after birth. Affected infants achieve no developmental milestones and die within the first months or years of life (summary by Saitsu et al., 2014).

Clinical Features

Puffenberger et al. (2012) reported 3 patients from 3 different Amish sibships in Pennsylvania with a lethal neonatal neurologic disorder. Episodic jerking was apparent in utero. At birth, affected individuals had small heads (1.5-2.0 SD below normal), overlapping cranial sutures, small or absent fontanels, and depressed frontal bones. The hands were fisted and there was extreme axial and limb rigidity. The infants showed poorly responsive focal jerks of the tongue, face and arms in a nearly continuous sequence throughout life. Neuroimaging was normal or showed mild hypoplasia of the frontal lobes. Electroencephalograms (EEGs) were characterized by bilateral medium-high voltage spikes over the temporal and central regions, frequent multifocal seizures, background slowing, and no posterior rhythm. The infants made no developmental progress, and all died of cardiopulmonary arrest before age 4 months. Neuropathologic examination of the brain of 1 child showed neuronal loss with microglial reaction primarily in the striatum and cerebral cortex, consistent with corticobasal degeneration.

Saunders et al. (2012) reported a female infant from a consanguineous Mexican family with onset of intractable seizures 1 hour after birth. EEG showed focal epileptiform and sharp wave activity; brain imaging was normal. At 5 weeks of age, she had some dysmorphic features, including bitemporal narrowing, micrognathia, flat nasal bridge, upslanted palpebral fissures, and uplifted earlobes with redundant helices. She had hypertonia, hyperreflexia, persistence of cortical thumbs, clonus, and facial twitching. Respiratory support was withdrawn and the patient died in infancy. Two cousins reportedly died of intractable epilepsy in early infancy.

Straussberg et al. (2015) reported 2 sibs, born of consanguineous Arab parents, who presented with apneic episodes, interpreted to be seizures, on the first day of life. Other features included hypertonicity, scissoring, hyperreflexia, and upper limb contractures. Both patients developed intractable myoclonic seizures associated with EEG abnormalities. Brain imaging was normal in both patients. Neither achieved developmental milestones, and both died of cardiopulmonary arrest at 5 and 6 months of age.

Saitsu et al. (2014) reported 2 Japanese sisters, born of unrelated parents, with lethal neonatal rigidity and seizures. At or soon after birth, both patients were noted to have muscle hypertonia and dysmorphic facies, including round face, thin lips, and large ears in 1 patient. Both infants developed various intractable seizures, including tonic-clonic and myoclonic seizures, as well as apneic attacks. EEG showed a suppression-burst pattern in both patients, consistent with epileptic encephalopathy. Both patients also showed cerebral and cerebellar atrophy, a progressive decrease in head circumference, and optic atrophy. Neither achieved any developmental milestones, and they died at ages 3 months and 1 year. Brain imaging showed delayed myelination of the cerebral white matter in 1 patient. Postmortem examination of 1 patient showed neuronal loss in the cortex and cerebellum, moderate gliosis, and no myelination of the frontal lobes. The brainstem was relatively well preserved.

Van de Pol et al. (2015) reported 3 sibs, born of consanguineous Moroccan parents, with infantile onset of epileptic encephalopathy resulting in death between 2 and 17 months of age. Features included axial hypotonia, appendicular hypertonia, microcephaly, intractable seizures, absent development, severely abnormal EEG, and global brain atrophy. EEG showed abnormal background pattern, with multifocal sharp waves, frequent multifocal epileptic seizure activity, and burst-suppression pattern. Detailed neuropathologic examination performed on 1 infant showed global atrophy, enlarged ventricles, and thin corpus callosum. The neocortex showed normal 6-layer architecture, but there was a loss of neurons and intense reactive gliosis. Other findings included hippocampal sclerosis and neuronal loss and gliosis in the brainstem and cerebellum. The clinical features were similar to those reported by Puffenberger et al. (2012), and the patients reported by van de Pol et al. (2015) carried the same homozygous frameshift mutation in the BRAT1 gene (614506.0001).

Clinical Variability

Srivastava et al. (2016) reported a 15-month-old boy (patient 4), born of unrelated parents, with RMFSL who was still alive at the time of the report. He presented at birth with hypertonia and mild microcephaly, but developed head control and could sit and smile at 1 year of age. He developed refractory seizures associated with status epilepticus at age 4 months. Additional features included cortical visual impairment, dysphasia requiring G-tube placement, axial hypotonia, spasticity, and dysmorphic features, such as downslanting palpebral fissures, supraorbital fullness, flattened nose, low-set ears, and dry skin. Brain imaging showed mild cerebral volume loss, but normal cerebellum. Whole-exome sequencing identified compound heterozygous mutations in the BRAT1 gene (L140P, 614506.0009 and c.171delG, 614506.0010). The findings suggested a phenotypic spectrum associated with biallelic BRAT1 mutations.

Horn et al. (2016) reported 2 brothers, born of unrelated German parents, with RMFSL. One of the patients died at 2 months of age, whereas the other survived until almost 6 years of age. The infant who died at 2 months had classic features of the disorder, including neonatal onset of intractable seizures, feeding problems, increased muscle tone, recurrent apnea, and contractures. EEG showed diffuse slowing, bilateral spikes, a burst-suppression pattern, and focal status epilepticus. He did not reach any developmental milestones. The patient who survived developed intractable myoclonic seizures at 4 months of age, had axial hypotonia and appendicular hypertonia, was able to roll over, and had minimal head control, but did not progress from there. He also had contractures, impaired central vision, and no speech. Brain imaging showed thin corpus callosum, enlarged CSF spaces, and delayed myelination. Muscle biopsy showed immature myofibers and a severe reduction in cytochrome C oxidase levels, suggesting mitochondrial dysfunction. Targeted sequencing identified compound heterozygous mutations in the BRAT1 gene, c.638dupA (614506.0001) and a splice site mutation (c.1134+1G-A), which were confirmed by Sanger sequencing and segregated with the disorder in the family. Functional studies of the variants were not performed, but analysis of the father's fibroblasts (with the splice site mutation) showed a 40% reduction in BRAT1 expression compared to controls, suggesting a loss of function. The findings expanded the phenotypic spectrum of RMFSL even within the same family.

Inheritance

The transmission pattern of a lethal neonatal rigidity and multifocal seizure syndrome in the Amish families reported by Puffenberger et al. (2012) was consistent with autosomal recessive inheritance.

Molecular Genetics

By homozygosity mapping followed by exome sequencing of 2 Amish patients from Pennsylvania with lethal neonatal rigidity and multifocal seizure syndrome, Puffenberger et al. (2012) identified a homozygous truncating mutation in the BRAT1 gene (614506.0001). Two unrelated Old Order Amish infants from different demes in Wisconsin and Kentucky with a similar phenotype were found to carry the same homozygous mutation. Two heterozygous carriers of this mutation were found among 201 Old Order Amish control samples, yielding a population-specific allele frequency of 0.50%.

In a Mexican female infant (CMH172) with RMFSL, Saunders et al. (2012) identified a homozygous truncating mutation in the BRAT1 gene (614506.0002). The patient was part of a larger study of infants in the neonatal intensive care unit (NICU) who underwent rapid whole-genome sequencing with a 50-hour diagnostic yield time. Functional studies of the variant were not performed.

In a Japanese girl with RMFSL, Saitsu et al. (2014) identified compound heterozygous mutations in the BRAT1 gene (614506.0003 and 614506.0004). The mutations, which were found by exome sequencing, segregated with the disorder in the family.

In 2 sisters, born of consanguineous Arab parents, with RMFSL, Straussberg et al. (2015) identified a homozygous mutation in the BRAT1 gene (614506.0005). Both parents were heterozygous for the mutation.